tbuckley/cabot-search huggingface dataset:
DDEL-04. MODULATION OF THE BLOOD-TUMOR BARRIER FOR IMPROVED DRUG DELIVERY IN GLIOBLASTOMA
Authors: Jorge-Luis Jimenez-Macias, Zheyun Xu, Doug Anthony, Alex Brodsky, George Tollefson, William Hawkins, Andrea Schmidt, Michael Sun, Jason Hong, Megan Forrest, Michal Nowicki, Paul Bertone, Sean Lawler
Journal: Neuro-Oncology (2023)

Abstract Effective drug delivery remains a major challenge in glioblastoma (GBM) treatment. Specialized intercellular endothelial cell tight junctions at the blood-brain and blood-tumor barriers (BBB/BTB) represent obstacles to therapeutic efficacy by limiting intratumoral drug uptake. To understand the factors at the BTB that limit drug accessibility we performed bioinformatics analysis of TCGA data which suggested enrichment of the tight junction protein VE-cadherin (CDH5). CDH5 expression at the BTB was confirmed by immunostaining of patient GBM specimens and spatial transcriptomics using the 10X Visium platform. We found that a broadly selective protein kinase inhibitor, 6-bromoindirubin-3’-acetoxime (BIA), potently down-regulated CDH5 in cultured human cerebrovascular endothelial cells (HCMEC/D3) at the transcriptional level and this correlated with decreased trans-endothelial electrical resistance (TEER) measurement. In vivo administration of BIA (20 mg/kg IP) to mice bearing intracranial GBM xenografts showed striking downregulation of CDH5 in tumor associated endothelium. Furthermore, increased BTB permeability was shown using fluorescent tracers as well as DCE-MRI, which demonstrated elevated Ktrans values 24 hours after BIA administration. Integrated phospho-proteomic and transcriptomic analysis of BIA treated HCMEC/D3 cells support a mechanism involving p38 MAP kinase regulation of Ets-family transcription factors that drive CDH5 expression. At least a 20-fold increase in intra-tumoral accumulation of cisplatin and temozolomide was observed using G9-pCDH GBM xenografts when administered 24 h after BIA treatment. No increased drug uptake was seen in healthy brain tissue, indicating specific targeting of tumor vasculature. Efficacy studies showed extended survival when using cisplatin in combination with BIA (median 27d, p=0.0016) when compared to cisplatin (18.5d), BIA (21.5d) and control (18d). Further efficacy studies are underway. These data therefore identify the GBM-associated vasculature as a target for small molecule inhibition of tight junction formation to enhance intratumoral drug uptake. Ongoing studies are investigating the potential of this approach with a range of agents.
IMMU-32. CAN PEMBROLIZUMAB TREAT RECURRENT GLIOBLASTOMA AND REVERSE HIV LATENCY?
Authors: Jaspreet Kaur, William Silveira, Robert Loch MacDonald, Fan Mo, Silin Bao, Carlen Yuen
Journal: Neuro-Oncology (2023)

Abstract Immunotherapy revolutionized treatment for many solid tumors. Early studies show that immunotherapy may be effective for recurrent glioblastoma. The ongoing Phase 2 LEEP-005 clinical trial (pembrolizumab+lenvima) is currently enrolling glioblastoma patients, but excludes patients with HIV. However, there is a strong need to treat this special patient population. One of the barriers to achieving cure in HIV patients is HIV latency within infect CD4+ T cells. Recently published data suggests that pembrolizumab can reverse HIV latency by forcing the HIV out of intracellular hiding into the plasma where anti-retroviral therapy can be effective. We present a case of a 39 year-old male with HIV and a Left Parietal Glioblastoma who had progressive disease following a subtotal resection and radiation alone due persistent neutropenia. Post-radiation MR brain wwo showed progressive disease in the left parietal lobe and new dural-based lesions in the left frontal and temporal lobes. HIV viral load was &amp;lt; 20 and CD4 count was 406 on HAART. The patient declined lenvima, but was amenable to bevacizumab. At 1 month follow-up, after 1 infusion of pembrolizumab 200mg and 2 infusions of bevacizumab, he achieved CR in the original site of disease and stable disease in the left frontal and temporal lobes. HIV viral load was 52. CD4 count was 660. Though it is too early to draw any firm conclusions, in our patient, pembrolizumab appears to induce HIV reversal, which is supported by an increase in the increase in his HIV viral load. The combination of pembrolizumab and bevacizumab appears to be effective at short-term follow-up. Our study is significant because there is limited evidence on the use of PD-L1 inhibitors in active HIV patients with cancer. To our knowledge, our case is the first reported case of the use of pembrolizumab in a patient with HIV and glioblastoma.
IMMU-02. IS DUAL AGENT IMMUNOTHERAPY SHIFTING THE EPIDEMIOLOGY OF MELANOMA BRAIN METASTASES? A REAL-WORLD ANALYSIS AND SINGLE-INSTITUTION VALIDATION
Authors: Debarati Bhanja, Hannah Wilding, Camille Moeckel, Jinpyo Hong, Angel Baroz, Caleb Stahl, Ahmad Ozair, Joseph Dao, Jeff Sivik, Joseph Drabick, Colette Pameijer, Manmeet Ahluwalia, Alireza Mansouri
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Dual agent immunotherapy (dIT) has been paradigm changing in melanoma brain metastasis (MBM). Recent clinical trials have supported the role of dIT for upfront management of small, asymptomatic MBM. Yet, its potential role in extending brain metastasis free survival and decreasing MBM incidence overall has been inadequately explored. Objective: To compare new brain metastasis incidence, median overall survival (OS), and brain metastasis free survival (BMFS) in melanoma patients treated with dIT versus single immunotherapy (sIT). METHODS A real-world deidentified database collating clinical information from 92 organizations (TriNetX, Inc) was queried. Melanoma patients without brain metastases prior to immunotherapy were stratified by treatment (anti-CTLA4 [sIT] and combination anti-CTLA4/ anti-PD1 [dIT]) and propensity score matched. A complementary single-institution retrospective cohort study analyzed melanoma patients treated from 2012-2019. The incidence of new asynchronous MBMs after immunotherapy initiation was compared. Median OS and BMFS were compared via log-rank tests and Cox proportional-hazards model. RESULTS TriNetX identified 8,686 melanoma patients who received immunotherapy (4,585 dIT; 4,101 sIT). MBM prevalence was 9.6%, and 15.6%, for the dIT and sIT cohorts, respectively (p &amp;lt; 0.0001). DIT was associated with a lower likelihood of developing MBM compared to sIT (OR [95%CI], 0.64 [0.61-0.77]). After propensity score matching on demographics and significant comorbidities, OS was not statistically different between treatment groups. On single-institution analysis, 222 melanoma patients were included (89 dIT; 45 anti-CTLA4; 88 anti-PD1). Patients were predominantly stage III at diagnosis (43%) with PD-L1 expression (51%) and BRAF (43%), and NRAS wildtype (50%) mutational status. BMFS was significantly extended in the dIT cohort compared to the anti-CTLA4 or anti-PD1 alone cohorts (406, 217, 139 days, respectively; p&amp;lt; 0.0001). On Cox-proportional hazards model, no covariates significantly contributed to the BMFS difference. CONCLUSION These data highlight the impact of combination anti-CTL4/ anti-PD1 immunotherapy in decreasing BM incidence in melanoma.
PATH-28. OUTCOME IMPACT OF THE <i>CDKN2A/B HEMI</i>-ZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA
Authors: Ryosuke Otsuji, Nobuhiro Hata, Hidataka Yamamoto, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Naoki Noguchi, Akira Nakamizo, Masahiro Mizoguchi, Koji Yoshimoto
Journal: Neuro-Oncology (2023)

Abstract Homozygous deletion of CDKN2A/B is a strong adverse prognostic factor in IDH-mutant astrocytomas. However, the impact of hemizygous deletions is unknown. We investigated the impact of CDKN2A/B hemizygous deletions on prognosis. We enrolled 52 adult patients with IDH-mutant astrocytomas between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA) with threshold correction using a digital PCR-based IDH-mutant allele frequency. Immunohistochemical analysis of p16/MTAP was performed in CDKN2A/B deletion cases. Of the 52 cases, nine and three were classified as hemizygous and homozygous deletions, respectively. The OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS:38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p = 0.0191) and 2.44 (p = 0.0943) for homozygous and hemizygous deletions, respectively. Regarding PFS, in astrocytoma, the time to recurrence tended to be shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral, with a median PFS of 20.9, 38.9, and 53.0 months, respectively. There was no significant difference in PFS between the hemizygous deletion and copy-neutral groups (p = 0.4030). Malignant transformation was confirmed in 1 of 1 homozygous deletion, 2 of 3 hemizygous deletions, and 5 of 16 copy-neutrals. No significant difference was observed between the hemizygous deletion and copy-neutral groups; however, hemizygous deletion tended to require less time for malignant transformation than copy-neutral group (p = 0.1112). Immunohistochemistry revealed p16-negative and MTAP retention in cases with a hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In conclusion, CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytomas. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.
EXTH-72. TARGETED INHIBITION OF THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA INDUCES SENESCENCE THROUGH A MITOCHONDRIA-DEPENDENT MECHANISM
Authors: Chrysiida Baltira, Isabel Mayayo-Peralta, Miriam Guillen-Navarro, Ferhat Alkan, Bram Thijssen, Kimberley Pello, Daria Fedorushkova, Anna Their, Joana Silva, Fleur Jochems, Onno Bleijerveld, Hans Janssen, William Faller, Rene Bernards, Mark de Gooijer, Olaf van Tellingen
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a fatal brain tumor with a great unmet need for better therapies. Research on the genomic landscape of GBM has revealed that three major proliferation pathways — the PI3K-mTOR-AKT, the MAPK, and the CDK4/6-RB pathways — are overactive in the majority of GBM patients. Based on that knowledge we have developed a multi-target combination therapy (MTCT) by employing inhibitors of these three pathways. When these inhibitors are used in combination, lower, clinically more relevant concentrations of each drug are sufficient for target inhibition and proliferation arrest than with single agents. Excitingly, we find that MTCT not only shuts down proliferation but also causes permanent growth inhibition by the induction of senescence and the secretion of a senescence-associated secretory phenotype (SASP). MTCT-senescent cells have increased mitochondrial reactive oxygen species (mtROS). However, they do not acquire nuclear DNA damage but only local mitochondrial DNA damage. Addition of antioxidants that deplete mtROS resulted in senescence rescue both in terms of morphology and proliferation arrest. MTCT-senescent cells display an enhancement in total mitochondrial mass, mitochondrial DNA copy numbers, and the transcription of mitochondrial proteins. Despite this enhancement, the basal respiration rate of these cells is comparable to untreated cells, indicating an impaired maximal respiration capacity in MTCT-senescent cells. Concordantly, these cells display striking disturbances of their mitochondrial network. Intriguingly, depletion of functional mitochondria prevents the induction of mtROS and senescence by MTCT but not by classical senescence inducers such as ionizing radiation or high concentrations of CDK4/6 inhibitors. To conclude, MTCT induces senescence in GBM cells through a unique nuclear DNA damage-independent mechanism for which the mitochondria are essential.
QOL-23. BASELINE TOTAL BRAIN VOLUME PREDICTS FOR POORER QOL AND REDUCED OVERALL SURVIVAL AFTER CRANIAL RADIOTHERAPY IN OLDER PATIENTS WITH GLIOBLASTOMA (GBM): RESULTS FROM THE PROSPECTIVE BRITER STUDY
Authors: Cressida Lorimer, Anthony Chalmers, Samantha Mills, Gerard Thompson, Jennifer Glendenning, Isobelle Coombes, Juliet Brock
Journal: Neuro-Oncology (2023)

Abstract GBM incidence peaks in the 7th and 8th decades of life with prognosis worsening with age. Short-course partial brain radiotherapy, +/- chemotherapy, extends survival but there is no validated evidence for prediction of individual risk of acute radiotherapy related side effects. BRITER, a prospective multicentre observational trial, recruited patients with newly diagnosed GBM aged ≥ 65 planned for cranial radiotherapy. Baseline MRI scans were analysed for 5 putative markers of brain resilience including relative total brain volume (ratio of cerebrospinal fluid (CSF) volume to total intracranial volume (TIV)) and their relationship to change in QoL. 126 patients were enrolled; mean age 72 years (range 65-83); 67% men, 33% women. 4% had a radiological diagnosis, 19% biopsy and 77% had debulking surgery. 21% received palliative radiotherapy alone (25% 30Gy/6#, 75% 40Gy/15#), 79% received radiotherapy with concurrent TMZ (47% 40Gy/15#, 53% 60Gy/30#). Median OS was 11.3 months. After accounting for age, sex, treatment and baseline MoCA score, there was a significant relationship between baseline CSF:TIV ratio and change in QoL score at 8 weeks post treatment. For each unit point of increase in CSF:TIV ratio, there was a corresponding decrease in EORTC QLC C30 QoL score by a factor of 1.27 (coefficient -1.27, 95% CI -3.24 to -0.19 p = 0.02). 35 participants were too unwell to complete questionnaires or had died by the 8 week follow up visit. In this subgroup, post hoc logistic regression showed baseline CSF:TIV ratio was related to risk of non-attendance (OR 1.35, 95% CI 1.01-1.80, p = 0.04). Cox regression models were fitted for time to death in 88 participants who had analysable baseline MRI sequences. Baseline CSF:TIV was associated with worsened OS (HR 1.41, 95% CI 1.19-1.66, p &amp;lt; 0.001). This unique prospective study indicates that baseline imaging parameters can predict the impact of cranial radiotherapy on QoL and OS.
PATH-04. TRANSFORMATION OF GRADE 2 OLIGODENDROGLIOMA TO GLIOSARCOMA WITH RAPID AND EXTENSIVE PROGRESSION: CASE REPORT.
Authors: Ronak Jani, Eric Casinelli, Abhishek Goyal, Vikram Prabhu, Anupama Chundury, Ewa Borys, Kevin Barton, Jigisha Thakkar
Journal: Neuro-Oncology (2023)

Abstract Transition of WHO grade 2 oligodendroglioma to gliosarcoma is rare. We report a case of a 40 year-old gentleman with WHO grade 2 oligodendroglioma, isocitrate dehydrogenase enzyme (IDH)-mutant, 1p/19q co-deletion positive, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, tumor mutational burden of 5 mutations/megabase, with microsatellite stability. He underwent rapid and extensive transformation to WHO grade 4 glioblastoma with gliosarcomatous features, mesenchymal subclass on DNA methylation, IDH-wild type, 1p/19q co-deletion negative, MGMT promoter methylated. He was diagnosed with bi-hemispheric multifocal partially enhancing, T2-FLAIR hyperintense lesions. Pathology revealed WHO grade 2 oligodendroglioma. He enrolled on a clinical trial to receive proton radiation (45 Gray in 25 fractions) to the involved tumor sites. Three weeks after initiation of radiation, he developed headache, imbalance, and confusion. MRI brain 3 weeks after completion of radiation revealed worsening enhancement, edema, and a new region of non-enhancing T2-FLAIR hyperintensity. Bevacizumab was added for presumed pseudo-progression; followed by chemotherapy with procarbazine and lomustine (PC). Four cycles of PC were completed with observations of gradual clinical and radiographic worsening after each cycle. Re-resection of multifocal tumor for tissue diagnosis and tumor debulking revealed progression to WHO grade 3 oligodendroglioma with high mitotic activity and regions of palisading necrosis. Two weeks postoperatively, malignant cerebral edema developed, requiring left sided decompressive craniectomy. Despite early introduction of 2nd-line chemotherapy with temozolomide, his disease continued to progress and he succumbed 1.5 years after initial diagnosis. Autopsy revealed extensive bi-hemispheric involvement of WHO grade 4 glioblastoma. Our patient demonstrated unusually rapid clinical and radiographic progression within one month after completion of radiation. Other reported cases in the literature have documented progression at 1 to 5 years after initial treatment. Both IDH mutation and 1p19q co-deletion were lost in the gliosarcomatous transformation. This tumor did not respond to alkylating agents despite the MGMT promoter-methylated status.
CTIM-42. INB-200: PHASE 1 STUDY OF GENE MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)
Authors: Mina Lobbous, Trishna Goswami, Lawrence Lamb, Kate Rochlin, Thiumaine Pillay, Samantha Youngblood, Mariska ter Haak, Burt Nabors
Journal: Neuro-Oncology (2023)

Abstract γδ T cells target NKG2D ligands that are upregulated on tumor cells after chemotherapy exposure. IN8bio’s DeltEx drug resistant immunotherapy (DRI) are γδ T cells genetically engineered to express MGMT, conveying TMZ resistance to allow concomitant therapy. We present updated results from this Phase 1 trial, which enrolled adult newly diagnosed glioblastoma patients with adequate organ function, KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107) of DRI cells intratumorally with 150 mg/m2 of TMZ on Day (D) 1 of Stupp maintenance. The primary endpoint is safety and secondary endpoints include survival; immunologic and genomic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. 21 patients were enrolled, with 11 dosing (57% male; median age 68 (range: 21-76); 86% IDH-WT, 52% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS) or neurotoxicity (ICANS) reported. Most common adverse events were WBC/platelet count decreased, asthenia, headache, hydrocephalus, decreased appetite and balance disorder. C1 pts had PFS of 8.3, 11.9, 7.4 months (m) and OS of 15.6, 17.7 and 9.6m, respectively. In C2, 1 pt remains progression free at 26.4m, while one progressed at 22m and another died without relapse at 8.7m. C3 pt had a PFS of 7.1 and OS of 13.11m with other pts in dosing. γδ T cells successfully infused with peripheral TMZ-based lymphodepletion evidenced with near or below normal range T, B, and NK subsets for up to 1 year. DRI T cells have manageable toxicity with encouraging trend in PFS with enriched γδ T cell remaining despite peripheral lymphodepletion.
EXTH-16. DEVELOPMENT OF INTRATHECAL (IT) DRUG DELIVERY PLATFORM TO CURE BREAST CANCER (BC) LEPTOMENINGEAL DISEASE (LMD) BY PEPTIDE-PULSED TYPE 1 CONVENTIONAL DENDRITIC CELL (CDC1) VACCINE IN PRECLINICAL MODEL
Authors: Vincent Law, Colin Snyder, Lauren Macaisa, Saurabh Garg, Brian Czerniecki, Peter Forsyth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND LMD is a rare form of metastasis in the meninges. Approximately 5% of advanced stage BC will develop LMD and currently there is no cure. One of the major hurdles is drug penetration due to the blood brain barrier (BBB) and blood-cerebral spinal fluid (CSF)-barrier. While the Ommaya reservoir is used clinically to overcome this challenge, there has not been an optimized preclinical model that allows researchers to adequately test novel therapies in the CSF space. METHODS The Forsyth lab have recently developed an MRI-compatible device called the “murine Ommaya” which mimics the Ommaya reservoir and allows repeated IT administration of drugs in minute 3-7 μL directly into CSF, bypassing BBB. In a joint effort with Dr. Czerniecki, whose lab have developed a pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and subsequently generating tumor-targeting cDC1s, we have created a platform to IT deliver peptide-pulsed cDC1 immunotherapy directly targeting BC-LMD. RESULTS Currently, we have tested the efficacy of treatment in HER2+ LMD and triple negative breast cancer (TNBC) LMD models and found a very favorable response; LMD mice that received IT cDC1 therapy showed tumor regression and their survival were significantly prolonged. About 70% of mice from HER2+ LMD and 30% from TNBC LMD were eventually disease-free. Cured mice also exhibited resistance against LMD recurrence. CONCLUSIONS Our preliminary data suggest IT cDC1 vaccine is effective against the incurable BC-LMD. We are currently investigating the mechanism(s) by which IT cDC1-initiated CD4 Th1 adaptive immune response against LMD. By using single-cell RNA-sequencing technique, we are analyzing the immune landscape in CSF tumor microenvironment in response to IT cDC1. FDA-approved phase 1 clinical trial has been funded by the DOD. Future approach includes employing our IT cDC1 immunotherapy platform in other cancer types, such as LMD from melanoma.
EXTH-10. QUAD-DM1: A HIGHLY POTENT DRUG CONJUGATE FOR BREAST CANCER AND BREAST CANCER BRAIN METASTASIS TREATMENT
Authors: Waldemar Debinski, Kaitlin N Fink, John Rossmeisl, Ryan T Mott, Denise Herpai
Journal: Neuro-Oncology (2023)

Abstract Triple-negative breast cancer (TNBC) remains an unmet need in medicine. Previously, we and others found that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed in almost all patients with glioblastoma (GBM). We performed a first-of-a-kind Phase I clinical trial in dogs with spontaneous gliomas using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. The majority of dogs experienced &amp;gt;50% of tumor regression; four dogs exhibited &amp;gt;92% tumor shrinkage and several dogs became long-term survivors. Next, we pursued the novel idea of targeting four tumor-associated receptors, instead of two, with one pharmaceutical compound. To this end, we produced a multivalent ligand, termed QUAD. More recently, we found that a conjugate of QUAD with emtansine (DM1), a microtubule-disrupting agent, demonstrated a specific killing potency on GBM cells, in low picomolar range. Unexpectedly, we observed that human breast cancer cells are also highly responsive to this drug candidate. We thus examined the presence of the four receptors in breast cancer cells and tissue micro-arrays, including involved lymph nodes, and in paired primary tumor - brain metastases, spanning two molecular subtypes of breast cancer: TNBC and HER2+. We found that the four targeted receptors are expressed in almost all breast cancer and related metastases to brain specimens, based on the expression levels for the genes and the gene products. Furthermore, the breast cancer cell lines like HC1806, MDA-MB-468, MDA-MB-231, BT549, and the breast metastatic cell line MDA-MB-231-BRM cells are killed at up to picomolar concentrations of QUAD-DM1. MDA-MB-231 tumors growing in mammary pads of athymic mice responded significantly to QUAD-DM1 given intravenously; QUAD recognizes murine receptors similarly to human. Thus, QUAD-DM1 is a novel type of a multivalent drug conjugate for the treatment of breast cancer and its brain metastases, which is applicable, but not exclusively, to TNBC.